Silibinin Induces Both Apoptosis and Necroptosis with Potential Anti-tumor Efficacy in Lung Cancer
  • * (Excluding Mailing and Handling)

Abstract

Background: Lung cancer incidence is steadily on the rise, posing a growing threat to human health. The search for therapeutic drugs from natural active substance and elucidating their mechanism have been the focus of anti-tumor research.

Objective: In our work, Silibinin (SiL) was chosen as a possible substance that could inhibit lung cancer. and its effects on inducing tumor cell death have been studied.

Methods: CCK-8 analysis and morphological observation were used to assess the cytotoxic impacts of SiL on lung cancer cells in vitro. The alterations in mitochondrial membrane potential (MMP) and apoptosis rate of cells were detected by flow cytometry. The level of lactate dehydrogenase (LDH) release out of cells was measured. The expression changes of apoptosis or necroptosis-related proteins were detected using western blotting. Protein interactions among RIPK1, RIPK3 and MLKL were analyzed using the co-immunoprecipitation technique. In vivo, SiL was evaluated for its antitumor effects using LLC tumor-bearing mice with mouse lung cancer.

Results: With an increased dose of SiL, the proliferation ability of A549 cells was considerably inhibited, and the accompanying cell morphology changed. The results of flow cytometry showed that after SiL treatment, MMP levels decreased, and the proportion of cells undergoing apoptosis increased. The proteins associated with apoptosis were upregulated and activated. The amount of LDH released from the cells increased following SiL treatment, accompanied by augmented expression and phosphorylation levels of necroptosis-related proteins. The co-IP assay further confirmed necrosome formation induced by SiL. Furthermore, Necrosulfonamide (an MLKL inhibitor) increased the apoptotic rate of SiL-treated cells and aggravated the cytotoxic effect of SiL, indicating that necroptosis blockade could switch cell death to apoptosis and increase the inhibitory effect of SiL on A549 cells. In LLC-bearing mice, gastric administration of SiL significantly inhibited tumor growth.

Conclusions: This study helped clarify the anti-tumor mechanism of SiL against lung cancer, elucidating its role in dual induction of apoptosis and necroptosis. In particular, necroptosis blockade could switch cell death to apoptosis and increase the inhibitory effect of SiL. Our work provided an experimental basis for the research on cell death induced by SiL and revealed its possible applications for improving the management of lung cancer.

[1]
Bray, F.; Laversanne, M.; Sung, H.; Ferlay, J.; Siegel, R.L.; Soerjomataram, I.; Jemal, A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2024, 74(3), 229-263.
[http://dx.doi.org/10.3322/caac.21834] [PMID: 38572751]
[2]
Sahu, P.; Donovan, C.; Paudel, K.R.; Pickles, S.; Chimankar, V.; Kim, R.Y.; Horvart, J.C.; Dua, K.; Ieni, A.; Nucera, F.; Bielefeldt-Ohmann, H.; Mazilli, S.; Caramori, G.; Lyons, J.G.; Hansbro, P.M. Pre-clinical lung squamous cell carcinoma mouse models to identify novel biomarkers and therapeutic interventions. Front. Oncol., 2023, 13, 1260411.
[http://dx.doi.org/10.3389/fonc.2023.1260411] [PMID: 37817767]
[3]
Ando, K.; Kishino, Y.; Homma, T.; Kusumoto, S.; Yamaoka, T.; Tanaka, A.; Ohmori, T.; Ohnishi, T.; Sagara, H. Nivolumab plus Ipilimumab versus existing immunotherapies in patients with PD-L1-positive advanced non-small cell lung cancer: A systematic review and network meta-analysis. Cancers (Basel), 2020, 12(7), 1905.
[http://dx.doi.org/10.3390/cancers12071905] [PMID: 32679702]
[4]
Lemjabbar-Alaoui, H.; Hassan, O.U.; Yang, Y.W.; Buchanan, P. Lung cancer: Biology and treatment options. Biochim. Biophys. Acta, 2015, 1856(2), 189-210.
[PMID: 26297204]
[5]
Mott, T.F. Lung Cancer: Management. FP Essent., 2018, 464, 27-30.
[PMID: 29313655]
[6]
Hirsch, F.R.; Scagliotti, G.V.; Mulshine, J.L.; Kwon, R.; Curran, W.J., Jr; Wu, Y.L.; Paz-Ares, L. Lung cancer: current therapies and new targeted treatments. Lancet, 2017, 389(10066), 299-311.
[http://dx.doi.org/10.1016/S0140-6736(16)30958-8] [PMID: 27574741]
[7]
Shi, K.; Wang, G.; Pei, J.; Zhang, J.; Wang, J.; Ouyang, L.; Wang, Y.; Li, W. Emerging strategies to overcome resistance to third-generation EGFR inhibitors. J. Hematol. Oncol., 2022, 15(1), 94.
[http://dx.doi.org/10.1186/s13045-022-01311-6] [PMID: 35840984]
[8]
Singh, S.; Sadhukhan, S.; Sonawane, A. 20 years since the approval of first EGFR-TKI, gefitinib: Insight and foresight. Biochim. Biophys. Acta Rev. Cancer, 2023, 1878(6), 188967.
[http://dx.doi.org/10.1016/j.bbcan.2023.188967] [PMID: 37657684]
[9]
Zhang, J.; Liu, S.; Chen, X.; Xu, X.; Xu, F. Non-immune cell components in tumor microenvironment influencing lung cancer Immunotherapy. Biomed. Pharmacother., 2023, 166, 115336.
[http://dx.doi.org/10.1016/j.biopha.2023.115336] [PMID: 37591126]
[10]
Zhang, M.; Chen, X.; Radacsi, N. New tricks of old drugs: Repurposing non-chemo drugs and dietary phytochemicals as adjuvants in anti-tumor therapies. J. Control. Release, 2021, 329, 96-120.
[http://dx.doi.org/10.1016/j.jconrel.2020.11.047] [PMID: 33259852]
[11]
Al-Yozbaki, M.; Wilkin, P.J.; Gupta, G.K.; Wilson, C.M. Therapeutic potential of natural compounds in lung cancer. Curr. Med. Chem., 2021, 28(39), 7988-8002.
[http://dx.doi.org/10.2174/0929867328666210322103906] [PMID: 33749551]
[12]
Naeem, A.; Hu, P.; Yang, M.; Zhang, J.; Liu, Y.; Zhu, W.; Zheng, Q. Natural products as anticancer agents: Current status and future perspectives. Molecules, 2022, 27(23), 8367.
[http://dx.doi.org/10.3390/molecules27238367] [PMID: 36500466]
[13]
Talib, W.H.; Awajan, D.; Hamed, R.A.; Azzam, A.O.; Mahmod, A.I. AL-Yasari, I.H. Combination anticancer therapies using selected phytochemicals. Molecules, 2022, 27(17), 5452.
[http://dx.doi.org/10.3390/molecules27175452] [PMID: 36080219]
[14]
Bosch-Barrera, J.; Queralt, B.; Menendez, J.A. Targeting STAT3 with silibinin to improve cancer therapeutics. Cancer Treat. Rev., 2017, 58, 61-69.
[http://dx.doi.org/10.1016/j.ctrv.2017.06.003] [PMID: 28686955]
[15]
Fanoudi, S.; Alavi, M.S.; Karimi, G.; Hosseinzadeh, H. Milk thistle (Silybum Marianum) as an antidote or a protective agent against natural or chemical toxicities: A review. Drug Chem. Toxicol., 2020, 43(3), 240-254.
[http://dx.doi.org/10.1080/01480545.2018.1485687] [PMID: 30033764]
[16]
Křen, V.; Valentová, K. Silybin and its congeners: from traditional medicine to molecular effects. Nat. Prod. Rep., 2022, 39(6), 1264-1281.
[http://dx.doi.org/10.1039/D2NP00013J] [PMID: 35510639]
[17]
Abenavoli, L.; Izzo, A.A.; Milić, N.; Cicala, C.; Santini, A.; Capasso, R. Milk thistle (Silybum marianum): A concise overview on its chemistry, pharmacological, and nutraceutical uses in liver diseases. Phytother. Res., 2018, 32(11), 2202-2213.
[http://dx.doi.org/10.1002/ptr.6171] [PMID: 30080294]
[18]
Wadhwa, K.; Pahwa, R.; Kumar, M.; Kumar, S.; Sharma, P.C.; Singh, G.; Verma, R.; Mittal, V.; Singh, I.; Kaushik, D.; Jeandet, P. Mechanistic insights into the pharmacological significance of Silymarin. Molecules, 2022, 27(16), 5327.
[http://dx.doi.org/10.3390/molecules27165327] [PMID: 36014565]
[19]
Zi, X.; Grasso, A.W.; Kung, H.J.; Agarwal, R. A flavonoid antioxidant, silymarin, inhibits activation of erbB1 signaling and induces cyclin-dependent kinase inhibitors, G1 arrest, and anticarcinogenic effects in human prostate carcinoma DU145 cells. Cancer Res., 1998, 58(9), 1920-1929.
[PMID: 9581834]
[20]
Zi, X.; Agarwal, R. Silibinin decreases prostate-specific antigen with cell growth inhibition via G 1 arrest, leading to differentiation of prostate carcinoma cells: Implications for prostate cancer intervention. Proc. Natl. Acad. Sci. USA, 1999, 96(13), 7490-7495.
[http://dx.doi.org/10.1073/pnas.96.13.7490] [PMID: 10377442]
[21]
Fallah, M.; Davoodvandi, A.; Nikmanzar, S.; Aghili, S.; Mirazimi, S.M.A.; Aschner, M.; Rashidian, A.; Hamblin, M.R.; Chamanara, M.; Naghsh, N.; Mirzaei, H. Silymarin (milk thistle extract) as a therapeutic agent in gastrointestinal cancer. Biomed. Pharmacother., 2021, 142, 112024.
[http://dx.doi.org/10.1016/j.biopha.2021.112024] [PMID: 34399200]
[22]
Iqbal, M.A.; Chattopadhyay, S.; Siddiqui, F.A.; Ur Rehman, A.; Siddiqui, S.; Prakasam, G.; Khan, A.; Sultana, S.; Bamezai, R.N.K. Silibinin induces metabolic crisis in triple‐negative breast cancer cells by modulating EGFR‐MYC‐TXNIP axis: Potential therapeutic implications. FEBS J., 2021, 288(2), 471-485.
[http://dx.doi.org/10.1111/febs.15353] [PMID: 32356386]
[23]
Jafari, S.; Heydarian, S.; Lai, R.; Mehdizadeh, A.E.; Molavi, O. Silibinin induces immunogenic cell death in cancer cells and enhances the induced immunogenicity by chemotherapy. Bioimpacts, 2023, 13(1), 51-61.
[http://dx.doi.org/10.34172/bi.2022.23698] [PMID: 36816998]
[24]
Tuli, H.S.; Mittal, S.; Aggarwal, D.; Parashar, G.; Parashar, N.C.; Upadhyay, S.K.; Barwal, T.S.; Jain, A.; Kaur, G.; Savla, R.; Sak, K.; Kumar, M.; Varol, M.; Iqubal, A.; Sharma, A.K. Path of Silibinin from diet to medicine: A dietary polyphenolic flavonoid having potential anti-cancer therapeutic significance. Semin. Cancer Biol., 2021, 73, 196-218.
[http://dx.doi.org/10.1016/j.semcancer.2020.09.014] [PMID: 33130037]
[25]
Verdura, S.; Cuyàs, E.; Ruiz-Torres, V.; Micol, V.; Joven, J.; Bosch-Barrera, J.; Menendez, J.A. Lung cancer management with silibinin: A historical and translational perspective. Pharmaceuticals (Basel), 2021, 14(6), 559.
[http://dx.doi.org/10.3390/ph14060559] [PMID: 34208282]
[26]
Si, L.; Fu, J.; Liu, W.; Hayashi, T.; Mizuno, K.; Hattori, S.; Fujisaki, H.; Onodera, S.; Ikejima, T. Silibinin-induced mitochondria fission leads to mitophagy, which attenuates silibinin-induced apoptosis in MCF-7 and MDA-MB-231 cells. Arch. Biochem. Biophys., 2020, 685108284.
[http://dx.doi.org/10.1016/j.abb.2020.108284] [PMID: 32014401]
[27]
Mao, Y.X.; Cai, W.J.; Sun, X.Y.; Dai, P.P.; Li, X.M.; Wang, Q.; Huang, X.L.; He, B.; Wang, P.P.; Wu, G.; Ma, J.F.; Huang, S.B. RAGE-dependent mitochondria pathway: a novel target of silibinin against apoptosis of osteoblastic cells induced by advanced glycation end products. Cell Death Dis., 2018, 9(6), 674.
[http://dx.doi.org/10.1038/s41419-018-0718-3] [PMID: 29867140]
[28]
Ham, J.; Lim, W.; Bazer, F.W.; Song, G. Silibinin stimluates apoptosis by inducing generation of ROS and ER stress in human choriocarcinoma cells. J. Cell. Physiol., 2018, 233(2), 1638-1649.
[http://dx.doi.org/10.1002/jcp.26069] [PMID: 28657208]
[29]
Zeng, J.; Sun, Y.; Wu, K.; Li, L.; Zhang, G.; Yang, Z.; Wang, Z.; Zhang, D.; Xue, Y.; Chen, Y.; Zhu, G.; Wang, X.; He, D. Chemopreventive and chemotherapeutic effects of intravesical silibinin against bladder cancer by acting on mitochondria. Mol. Cancer Ther., 2011, 10(1), 104-116.
[http://dx.doi.org/10.1158/1535-7163.MCT-10-0577] [PMID: 21220495]
[30]
Sameri, S.; Mohammadi, C.; Mehrabani, M.; Najafi, R. Targeting the hallmarks of cancer: the effects of silibinin on proliferation, cell death, angiogenesis, and migration in colorectal cancer. BMC Complementary Med. Ther., 2021, 21(1), 160.
[http://dx.doi.org/10.1186/s12906-021-03330-1] [PMID: 34059044]
[31]
Jahanafrooz, Z.; Motamed, N.; Rinner, B.; Mokhtarzadeh, A.; Baradaran, B. Silibinin to improve cancer therapeutic, as an apoptotic inducer, autophagy modulator, cell cycle inhibitor, and microRNAs regulator. Life Sci., 2018, 213, 236-247.
[http://dx.doi.org/10.1016/j.lfs.2018.10.009] [PMID: 30308184]
[32]
Mateen, S.; Raina, K.; Agarwal, R. Chemopreventive and anti-cancer efficacy of silibinin against growth and progression of lung cancer. Nutr. Cancer, 2013, 65(Suppl. 1), 3-11.
[http://dx.doi.org/10.1080/01635581.2013.785004]
[33]
Lins, F.V.; Bispo, E.C.I.; Rodrigues, N.S.; Silva, M.V.S.; Carvalho, J.L.; Gelfuso, G.M.; Saldanha-Araujo, F. Ibrutinib modulates proliferation, migration, mitochondrial homeostasis, and apoptosis in melanoma Cells. Biomedicines, 2024, 12(5), 1012.
[http://dx.doi.org/10.3390/biomedicines12051012] [PMID: 38790974]
[34]
Rostampour, S.; Eslami, F.; Babaei, E.; Mostafavi, H.; Mahdavi, M. An active compound from the pyrazine family induces apoptosis by targeting the Bax/Bcl2 and Survivin expression in chronic myeloid leukemia K562 cells. Anticancer. Agents Med. Chem., 2024, 24(3), 203-212.
[http://dx.doi.org/10.2174/0118715206272359231121105713] [PMID: 38038011]
[35]
Özerkan, D. The Determination of cisplatin and luteolin synergistic effect on colorectal cancer cell apoptosis and mitochondrial dysfunction by fluorescence labelling. J. Fluoresc., 2023, 33(3), 1217-1225.
[http://dx.doi.org/10.1007/s10895-023-03145-y] [PMID: 36652047]
[36]
Zhang, L.N.; Xia, Y.Z.; Zhang, C.; Zhang, H.; Luo, J.G.; Yang, L.; Kong, L.Y. Vielanin K enhances doxorubicin-induced apoptosis via activation of IRE1α- TRAF2 - JNK pathway and increases mitochondrial Ca2 + influx in MCF-7 and MCF-7/MDR cells. Phytomedicine, 2020, 78, 153329.
[http://dx.doi.org/10.1016/j.phymed.2020.153329] [PMID: 32896708]
[37]
Zang, W.; Cao, H.; Ge, J.; Zhao, D. Structures, physical properties and antibacterial activity of silver nanoparticles of Lactiplantibacillus plantarum exopolysaccharide. Int. J. Biol. Macromol., 2024, 263(Pt 2), 130083.
[http://dx.doi.org/10.1016/j.ijbiomac.2024.130083] [PMID: 38423905]
[38]
Delmas, D.; Xiao, J.; Vejux, A.; Aires, V. Silymarin and cancer: A dual strategy in both in chemoprevention and chemosensitivity. Molecules, 2020, 25(9), 2009.
[http://dx.doi.org/10.3390/molecules25092009] [PMID: 32344919]
[39]
Degterev, A.; Huang, Z.; Boyce, M.; Li, Y.; Jagtap, P.; Mizushima, N.; Cuny, G.D.; Mitchison, T.J.; Moskowitz, M.A.; Yuan, J. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat. Chem. Biol., 2005, 1(2), 112-119.
[http://dx.doi.org/10.1038/nchembio711] [PMID: 16408008]
[40]
Ai, Y.; Meng, Y.; Yan, B.; Zhou, Q.; Wang, X. The biochemical pathways of apoptotic, necroptotic, pyroptotic, and ferroptotic cell death. Mol. Cell, 2024, 84(1), 170-179.
[http://dx.doi.org/10.1016/j.molcel.2023.11.040] [PMID: 38181758]
[41]
Wendlocha, D.; Kubina, R.; Krzykawski, K.; Mielczarek-Palacz, A. Selected flavonols targeting cell death pathways in cancer therapy: The latest achievements in research on apoptosis, autophagy, necroptosis, pyroptosis, ferroptosis, and cuproptosis. Nutrients, 2024, 16(8), 1201.
[http://dx.doi.org/10.3390/nu16081201] [PMID: 38674891]
[42]
Shi, Y.; Wu, C.; Shi, J.; Gao, T.; Ma, H.; Li, L.; Zhao, Y. Protein phosphorylation and kinases: Potential therapeutic targets in necroptosis. Eur. J. Pharmacol., 2024, 970, 176508.
[http://dx.doi.org/10.1016/j.ejphar.2024.176508] [PMID: 38493913]
[43]
Green, D.R. The coming decade of cell death research: Five riddles. Cell, 2019, 177(5), 1094-1107.
[http://dx.doi.org/10.1016/j.cell.2019.04.024] [PMID: 31100266]
[44]
Sun, L.; Wang, H.; Wang, Z.; He, S.; Chen, S.; Liao, D.; Wang, L.; Yan, J.; Liu, W.; Lei, X.; Wang, X. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell, 2012, 148(1-2), 213-227.
[http://dx.doi.org/10.1016/j.cell.2011.11.031] [PMID: 22265413]
[45]
McNamara, D.E.; Quarato, G.; Guy, C.S.; Green, D.R.; Moldoveanu, T. Characterization of MLKL-mediated plasma membrane rupture in necroptosis. J. Vis. Exp., 2018, (138), 58088.
[PMID: 30148498]
[46]
Yang, Y.; Xie, E.; Du, L.; Yang, Y.; Wu, B.; Sun, L.; Wang, S.; OuYang, B. Positive Charges in the Brace Region Facilitate the Membrane Disruption of MLKL-NTR in Necroptosis. Molecules, 2021, 26(17), 5194.
[http://dx.doi.org/10.3390/molecules26175194] [PMID: 34500630]
[47]
Weinelt, N.; Wächtershäuser, K.N.; Celik, G.; Jeiler, B.; Gollin, I.; Zein, L.; Smith, S.; Andrieux, G.; Das, T.; Roedig, J.; Feist, L.; Rotter, B.; Boerries, M.; Pampaloni, F.; van Wijk, S.J.L. LUBAC-mediated M1 Ub regulates necroptosis by segregating the cellular distribution of active MLKL. Cell Death Dis., 2024, 15(1), 77.
[http://dx.doi.org/10.1038/s41419-024-06447-6] [PMID: 38245534]
[48]
Ramirez, R.X.; Campbell, O.; Pradhan, A.J.; Atilla-Gokcumen, G.E.; Monje-Galvan, V. Modeling the molecular fingerprint of protein-lipid interactions of MLKL on complex bilayers. Front Chem., 2023, 10, 1088058.
[http://dx.doi.org/10.3389/fchem.2022.1088058] [PMID: 36712977]
[49]
Zhao, J.; Jitkaew, S.; Cai, Z.; Choksi, S.; Li, Q.; Luo, J.; Liu, Z.G. Mixed lineage kinase domain-like is a key receptor interacting protein 3 downstream component of TNF-induced necrosis. Proc. Natl. Acad. Sci. USA, 2012, 109(14), 5322-5327.
[http://dx.doi.org/10.1073/pnas.1200012109] [PMID: 22421439]
[50]
Wang, N.; Li, C.Y.; Yao, T.F.; Kang, X.D.; Guo, H.S. OSW-1 triggers necroptosis in colorectal cancer cells through the RIPK1/RIPK3/MLKL signaling pathway facilitated by the RIPK1-p62/SQSTM1 complex. World J. Gastroenterol., 2024, 30(15), 2155-2174.
[http://dx.doi.org/10.3748/wjg.v30.i15.2155] [PMID: 38681991]
[51]
Guan, S.; Qu, X.; Wang, J.; Zhang, D.; Lu, J. 3-Monochloropropane-1,2-diol esters induce HepG2 cells necroptosis via CTSB/TFAM/ROS pathway. Food Chem. Toxicol., 2024, 186114525.
[http://dx.doi.org/10.1016/j.fct.2024.114525] [PMID: 38408632]
[52]
Zhang, Y.; Zhou, X. Targeting regulated cell death (RCD) in hematological malignancies: Recent advances and therapeutic potential. Biomed. Pharmacother., 2024, 175, 116667.
[http://dx.doi.org/10.1016/j.biopha.2024.116667] [PMID: 38703504]
[53]
Liu, R.J.; Yu, X.D.; Yan, S.S.; Guo, Z.W.; Zao, X.B.; Zhang, Y.S. Ferroptosis, pyroptosis and necroptosis in hepatocellular carcinoma immunotherapy: Mechanisms and immunologic landscape (Review). Int. J. Oncol., 2024, 64(6), 63.
[http://dx.doi.org/10.3892/ijo.2024.5651] [PMID: 38757345]
[54]
Najafov, A.; Chen, H.; Yuan, J. Necroptosis and cancer. Trends Cancer, 2017, 3(4), 294-301.
[http://dx.doi.org/10.1016/j.trecan.2017.03.002] [PMID: 28451648]
[55]
Yan, J.; Wan, P.; Choksi, S.; Liu, Z.G. Necroptosis and tumor progression. Trends Cancer, 2022, 8(1), 21-27.
[http://dx.doi.org/10.1016/j.trecan.2021.09.003] [PMID: 34627742]
[56]
Zang, X.; Song, J.; Li, Y.; Han, Y. Targeting necroptosis as an alternative strategy in tumor treatment: From drugs to nanoparticles. J. Control. Release, 2022, 349, 213-226.
[http://dx.doi.org/10.1016/j.jconrel.2022.06.060] [PMID: 35793737]
[57]
Liu, Z.; Jiao, D. Necroptosis, tumor necrosis and tumorigenesis. Cell Stress, 2020, 4(1), 1-8.
[http://dx.doi.org/10.15698/cst2020.01.208] [PMID: 31922095]
[58]
Qin, Y.; Sheng, Y.; Ren, M.; Hou, Z.; Xiao, L.; Chen, R. Identification of necroptosis-related gene signatures for predicting the prognosis of ovarian cancer. Sci. Rep., 2024, 14(1), 11133.
[http://dx.doi.org/10.1038/s41598-024-61849-y] [PMID: 38750159]
[59]
Chong, L.H.; Yip, A.K.; Farm, H.J.; Mahmoud, L.N.; Zeng, Y.; Chiam, K.H. The role of cell-matrix adhesion and cell migration in breast tumor growth and progression. Front. Cell Dev. Biol., 2024, 121339251.
[http://dx.doi.org/10.3389/fcell.2024.1339251] [PMID: 38374894]
[60]
Höckendorf, U.; Yabal, M.; Herold, T.; Munkhbaatar, E.; Rott, S.; Jilg, S.; Kauschinger, J.; Magnani, G.; Reisinger, F.; Heuser, M.; Kreipe, H.; Sotlar, K.; Engleitner, T.; Rad, R.; Weichert, W.; Peschel, C.; Ruland, J.; Heikenwalder, M.; Spiekermann, K.; Slotta-Huspenina, J.; Groß, O.; Jost, P.J. RIPK3 restricts myeloid leukemogenesis by promoting cell death and differentiation of leukemia initiating cells. Cancer Cell, 2016, 30(1), 75-91.
[http://dx.doi.org/10.1016/j.ccell.2016.06.002] [PMID: 27411587]
[61]
Seifert, L.; Werba, G.; Tiwari, S.; Giao Ly, N.N.; Alothman, S.; Alqunaibit, D.; Avanzi, A.; Barilla, R.; Daley, D.; Greco, S.H.; Torres-Hernandez, A.; Pergamo, M.; Ochi, A.; Zambirinis, C.P.; Pansari, M.; Rendon, M.; Tippens, D.; Hundeyin, M.; Mani, V.R.; Hajdu, C.; Engle, D.; Miller, G. The necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune suppression. Nature, 2016, 532(7598), 245-249.
[http://dx.doi.org/10.1038/nature17403] [PMID: 27049944]
[62]
Seehawer, M.; Heinzmann, F.; D’Artista, L.; Harbig, J.; Roux, P.F.; Hoenicke, L.; Dang, H.; Klotz, S.; Robinson, L.; Doré, G.; Rozenblum, N.; Kang, T.W.; Chawla, R.; Buch, T.; Vucur, M.; Roth, M.; Zuber, J.; Luedde, T.; Sipos, B.; Longerich, T.; Heikenwälder, M.; Wang, X.W.; Bischof, O.; Zender, L. Necroptosis microenvironment directs lineage commitment in liver cancer. Nature, 2018, 562(7725), 69-75.
[http://dx.doi.org/10.1038/s41586-018-0519-y] [PMID: 30209397]
[63]
Qin, X.; Ma, D.; Tan, Y.; Wang, H.; Cai, Z. The role of necroptosis in cancer: A double-edged sword? Biochim. Biophys. Acta Rev. Cancer, 2019, 1871(2), 259-266.
[http://dx.doi.org/10.1016/j.bbcan.2019.01.006] [PMID: 30716362]
[64]
Xue, Y.; Jiang, X.; Wang, J.; Zong, Y.; Yuan, Z.; Miao, S.; Mao, X. Effect of regulatory cell death on the occurrence and development of head and neck squamous cell carcinoma. Biomark. Res., 2023, 11(1), 2.
[http://dx.doi.org/10.1186/s40364-022-00433-w] [PMID: 36600313]
[65]
Scimeca, M.; Rovella, V.; Palumbo, V.; Scioli, M.P.; Bonfiglio, R.; Melino, G.; Piacentini, M.; Frati, L.; Agostini, M.; Candi, E.; Mauriello, A. Tor, Centre.; Melino, G.; Piacentini, M.; Frati, L.; Agostini, M.; Candi, E.; Mauriello, A. Programmed cell death pathways in cholangiocarcinoma: Opportunities for targeted therapy. Cancers (Basel), 2023, 15(14), 3638.
[http://dx.doi.org/10.3390/cancers15143638] [PMID: 37509299]
[66]
Thijssen, R.; Alvarez-Diaz, S.; Grace, C.; Gao, M.; Segal, D.H.; Xu, Z.; Strasser, A.; Huang, D.C.S. Loss of RIPK3 does not impact MYC-driven lymphomagenesis or chemotherapeutic drug-induced killing of malignant lymphoma cells. Cell Death Differ., 2020, 27(8), 2531-2533.
[http://dx.doi.org/10.1038/s41418-020-0576-2] [PMID: 32555451]
[67]
Renaud, C.C.N.; Nicolau, C.A.; Maghe, C.; Trillet, K.; Jardine, J.; Escot, S.; David, N.; Gavard, J.; Bidère, N. Necrosulfonamide causes oxidation of PCM1 and impairs ciliogenesis and autophagy. iScience, 2024, 27(4), 109580.
[http://dx.doi.org/10.1016/j.isci.2024.109580] [PMID: 38600973]
[68]
Tang, Y.; Zhuang, C. Design, synthesis and anti-necroptosis activity of fused heterocyclic MLKL inhibitors. Bioorg. Med. Chem., 2024, 102, 117659.
[http://dx.doi.org/10.1016/j.bmc.2024.117659] [PMID: 38442525]
[69]
Oh, J.H.; Park, S.; Hong, E.; Choi, M.A.; Kwon, Y.M.; Park, J.; Lee, A.H.; Park, G.R.; Kim, H.Y.; Lee, S.M.; Lee, J.Y.; Bae, S.H.; Lee, J.H.; Lee, J.Y.; Jun, D.W. Novel inhibitor of mixed-lineage kinase domain-like protein: The antifibrotic effects of a necroptosis antagonist. ACS Pharmacol. Transl. Sci., 2023, 6(10), 1471-1479.
[http://dx.doi.org/10.1021/acsptsci.3c00131] [PMID: 37854622]
[70]
Tong, K.; Li, S.; Chen, G.; Ma, C.; Liu, X.; Liu, S.; Chen, N. Inhibition of neural stem cell necroptosis mediated by RIPK1/MLKL promotes functional recovery after SCI. Mol. Neurobiol., 2023, 60(4), 2135-2149.
[http://dx.doi.org/10.1007/s12035-022-03156-z] [PMID: 36602703]
[71]
Jiao, D.; Cai, Z.; Choksi, S.; Ma, D.; Choe, M.; Kwon, H.J.; Baik, J.Y.; Rowan, B.G.; Liu, C.; Liu, Z. Necroptosis of tumor cells leads to tumor necrosis and promotes tumor metastasis. Cell Res., 2018, 28(8), 868-870.
[http://dx.doi.org/10.1038/s41422-018-0058-y] [PMID: 29941926]
[72]
Liu, Z.; Choksi, S.; Kwon, H.J.; Jiao, D.; Liu, C.; Liu, Z. Tumor necroptosis-mediated shedding of cell surface proteins promotes metastasis of breast cancer by suppressing anti-tumor immunity. Breast Cancer Res., 2023, 25(1), 10.
[http://dx.doi.org/10.1186/s13058-023-01604-9] [PMID: 36703228]
[73]
Li, F.; Sun, H.; Yu, Y.; Che, N.; Han, J.; Cheng, R.; Zhao, N.; Guo, Y.; Huang, C.; Zhang, D. RIPK1-dependent necroptosis promotes vasculogenic mimicry formation via eIF4E in triple-negative breast cancer. Cell Death Dis., 2023, 14(5), 335.
[http://dx.doi.org/10.1038/s41419-023-05841-w] [PMID: 37217473]